Abstract 82: Macrophage Specific ABCA1 Deletion Does Not Worsen Insulin Resistance in High Fat Diet Induced or Genetic Obese Mouse Models

Abstract

Introduction Obesity associated low-grade, chronic inflammation underlies the pathogenesis of type 2 diabetes and insulin resistance. ATP-binding cassette transporter A1 (ABCA1), a membrane lipid transporter, forms nascent HDL particles by effluxing cellular free cholesterol (FC) and phospholipids to lipid-poor apolipoprotein A-I. In macrophages, ABCA1 also dampens pro-inflammatory MyD88-dependent Toll-like receptor signaling by reducing cellular membrane FC and lipid raft content, indicating a role for ABCA1 in macrophage-mediated innate immunity. However, the role of ABCA1 in macrophage-associated innate immunity in insulin resistance is unclear. Hypothesis We tested the hypothesis that macrophage-specific ABCA1 deletion may exacerbate insulin resistance by increasing obesity-induced chronic, low-grade inflammation. Methods and Results Wild type (WT) and macrophage-specific ABCA1 knockout (MSKO) mice in the C57/BL6 background were fed a 45% High Fat Diet (HFD) for 16-24 weeks or crossed into the leptin deficient (ob/ob) background to induce obesity. Our results showed that MSKO and WT mice developed obesity, insulin resistance, hypercholesterolemia, and hepatic steatosis to a similar extent with HFD feeding or after crossed into the ob/ob background. Resident peritoneal macrophages from HFD-fed or leptin deficient MSKO vs. WT mice accumulated significantly more cholesterol. Relative to chow, HFD markedly induced macrophage infiltration and inflammatory cytokine expression to a similar extent in adipose tissues in WT and MSKO mice. Among the examined pro-inflammatory cytokines in peritoneal macrophages, only IL-6 was highly up-regulated in ob/ob MSKO vs. WT control mice, indicating that lack of ABCA1 in macrophages does not significantly affect obesity associated chronic inflammation. Conclusion Although macrophage specific ABCA1 deficiency enhances Toll like receptor signaling, it does not significantly exacerbate obesity associated low grade, chronic inflammation, therefore has no impact on the pathogenesis of insulin resistance in both HFD induced and genetic obese mouse models.